Cancer kills many thousands of people annually throughout the world. There have been significant breakthroughs made in the treatment and prevention of a wide variety of cancers. For example breast cancer has seen early screening programs as well as a variety of surgical techniques. However, these often prove physically and emotionally debilitating. Moreover, patients who have undergone surgery and subsequent chemotherapy often experience a recurrence. In recent years research has indicated the heterogeneous tumorigenic potential of cancer cells which has lead to the cancer stem cell (CSC) hypothesis. In brief, this hypothesis states that only a fraction of cells within a tumor have stem cell like features, including unlimited proliferative potential.
Further evidence in the literature supports the concept that tumours are complex heterogeneous organ-like systems with a hierarchical cellular organization, rather than simply as collections of homogeneous single lineage tumour cells. The initiator tumour cell retains the capacity to generate diverse progeny at various levels of differentiation, from uncommitted pluripotent stem cells, to committed progenitor cells, to fully differentiated senescent descendent cells. In this way, the tumour cell population itself is heterogeneous, adding diverse architecture afforded by the immune, stromal, and vascular cells that are also present in tumours. Some of the cells within this “cancer organ” or tumour have the potential for continued proliferation. The phylogeny of these tumor cells thus suggests the existence of a cell population that retains the ability to self-renew while also often possessing the capacity to generate progeny that differentiate. Hence, the cancer stem cell is defined as being a cell within a tumour that possesses the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumour. Indeed laboratory evidence confirms that injection of isolated ovarian, brain, colon, breast, prostate or pancreatic cancer stem-like cells into immunocompromised mice results in the formation of tumours that are phenotypically identical to the original tumour and contain both stem-like cells and non-stem-like cells. Hence there are two distinct populations; a relatively well-differentiated subset with limited proliferative capacity forming the bulk of the tumor which phenotypically characterises the disease, and a second smaller, less differentiated subset that contains clonogenic CSCs. Importantly CSCs exhibit multiple-drug resistance, an additional property that contributes to their longevity and metastatic potential by permitting them to survive toxic insults, including many of the drugs currently used to treat cancer. There is therefore a need to develop therapies that specifically target the self-renewal capabilities of the stem cell population, thereby abrogating the source of tumour recurrence as a result of resistance to conventional therapies.
Putative CSC markers that have been described for other malignancies, including acute myeloid leukemia (CD34-positive/CD38-negative), breast (CD44-positive/CD24-negative/-low/Linnegative), prostate (CD44-positive/_2_1-high/CD133-positive) and brain (CD133-positive/nestinpositive), have reflected those expressed by their normal tissue counterparts' original status. Recent evidence confirms that CD44+ ovarian cancer cells also possess the ability to form tumours in immunocompromised mice. As with other CSC phenotypes, ovarian cancer stem cells are slow growing, chemoresistant and form tumours in immunocompromised mice that are phenotypically identical to the original tumour in that there are mainly CD44−ve cells forming the bulk of the tumour with small pockets of CD44+ve cells.
Many advanced cancers recur despite the use of chemotherapeutic and radiation modalities that initially lead to therapeutic responses. For example, irradiation of glioblastomas can lead to significant radiographic responses, yet these tumors invariably recur and lead to patient death. Frequently, glioblastomas recur in a nodular pattern, suggesting a clonal or polyclonal source of recurrent tumor cells that are able to withstand conventional cytotoxic therapies, including radiation therapy, to cause recurrence of disease. Furthermore, recurrent tumors also demonstrate heterogeneity within the tumor cell population with regard to the presence of both CSCs and non-CSCs as well as in histologic and cytogenetic differences. This suggests that the CSCs that populated the original tumor may have withstood therapeutic intervention to repopulate the recurrent tumor even after the bulk of the tumor had been removed by resection or chemoradiation therapy, hence the concept that CSCs are the source of post-therapeutic tumour recurrence. A shift in therapeutic strategy that leads to the development of unique targeted agents that attack CSCs may enhance cancer care and prolong the survival of many patients.
The present inventors have surprisingly discovered that a selection of benzopyran compounds are able to exert powerful biological effects on non-CSCs as well as CSCs. Such compounds offer alternative chemotherapeutic strategies for treating cancer and reducing the incidence or risk of cancer recurrence.